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Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation

A Corrigendum to this article was published on 18 December 2013

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Abstract

T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.

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Figure 1: Transport of amino acid by System L transporter in CD8+ T cells.
Figure 2: Amino acids and mTORC1 in CD8+ T cells.
Figure 3: Regulation of System L amino-acid transporters in T cells.
Figure 4: Characterization of Slc7a5fl/flCD4-Cre mice.
Figure 5: Effector differentiation of Slc7a5fl/flCD4-Cre T cells.
Figure 6: Activation and proliferation of Slc7a5fl/flCD4-Cre T cells.
Figure 7: Metabolic consequences of the deletion of Slc7a5 in T cells.

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Change history

  • 25 June 2013

    In the version of this article initially published, the legend for Figure 7b incorrectly included mutant cells. The correct legend should read "...OT-I lymph node T cells...." The error has been corrected in the HTML and PDF versions of the article.

References

  1. Wang, R. & Green, D.R. Metabolic checkpoints in activated T cells. Nat. Immunol. 13, 907–915 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Carr, E.L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037–1044 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Beugnet, A., Tee, A.R., Taylor, P.M. & Proud, C.G. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem. J. 372, 555 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Schriever, S.C., Deutsch, M.J., Adamski, J., Roscher, A.A. & Ensenauer, R. Cellular signaling of amino acids towards mTORC1 activation in impaired human leucine catabolism. J. Nutr. Biochem. 10.1016/j.jnutbio.2012.04.018 (2012).

  5. Zheng, Y. et al. Cells are metabolically anergic. J. Immunol. 183, 6095–6101 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Powell, J.D. & Delgoffe, G.M. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33, 301–311 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Rao, R.R., Li, Q., Odunsi, K. & Shrikant, P.A. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32, 67–78 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Sinclair, L.V. et al. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9, 513–521 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108–112 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Pearce, E.L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103–107 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kopf, H., la Rosa de, G.M., Howard, O.M.Z. & Chen, X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int. Immunopharmacol. 7, 1819–1824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Sauer, S. et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc. Natl. Acad. Sci. USA 105, 7797–7802 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Delgoffe, G.M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295–303 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Finlay, D.K. et al. PDK1/mTOR and Hypoxia-inducible factor 1 integrate metabolism and migration of CD8 T cells. J. Exp. Med. 209, 2441–2453 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Shi, L.Z. et al. HIF1 -dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J. Exp. Med. 208, 1367–1376 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871–882 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gottesdiener, K.M. et al. Isolation and structural characterization of the human 4F2 heavy-chain gene, an inducible gene involved in T-lymphocyte activation. Mol. Cell Biol. 8, 3809–3819 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lindsten, T., June, C.H., Thompson, C.B. & Leiden, J.M. Regulation of 4F2 heavy-chain gene expression during normal human T-cell activation can be mediated by multiple distinct molecular mechanisms. Mol. Cell Biol. 8, 3820–3826 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Parmacek, M.S., Karpinski, B.A., Gottesdiener, K.M., Thompson, C.B. & Leiden, J.M. Structure, expression and regulation of the murine 4F2 heavy chain. Nucleic Acids Res. 17, 1915–1931 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Verrey, F.O. et al. CATs and HATs: the SLC7 family of amino acid transporters. Pflügers Archive European. J. Physiol. 447, 532–542 (2004).

    Article  CAS  Google Scholar 

  21. Tsumura, H. et al. The targeted disruption of the CD98 gene results in embryonic lethality. Biochem. Biophys. Res. Commun. 308, 847–851 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Sato, Y., Heimeier, R.A., Li, C., Deng, C. & Shi, Y.-B. Extracellular domain of CD98hc is required for early murine development. Cell Biosci 1, 7 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Cantor, J. et al. CD98hc facilitates B cell proliferation and adaptive humoral immunity. Nat. Immunol. 10, 412–419 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Cantor, J., Slepak, M., Ege, N., Chang, J.T. & Ginsberg, M.H. Loss of T cell CD98 H chain specifically ablates T cell clonal expansion and protects from autoimmunity. J. Immunol. 187, 851–860 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Liu, Z. et al. Deletion of CD98 heavy chain in T cells results in cardiac allograft acceptance by increasing regulatory T cells. Transplantation 93, 1116–1124 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Usui, T. et al. Brasilicardin A, a natural immunosuppressant, targets amino acid transport System L. Chem. Biol. 13, 1153–1160 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Nicklin, P. et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136, 521–534 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Navarro, M.N. et al. Protein kinase D2 has a restricted but critical role in T-cell antigen receptor signalling in mature T-cells. Biochem. J. 442, 649–659 (2012).

    Article  CAS  PubMed  Google Scholar 

  29. Heng, T.S.P. et al. The Immunological Genome Project: networks of gene expression in immune cells. Nat. Immunol. 9, 1091–1094 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Ogilvy, S. et al. Promoter elements of vav drive transgene expression in vivo throughout the hematopoietic compartment. Blood 94, 1855–1863 (1999).

    Article  CAS  PubMed  Google Scholar 

  31. Hann, S.R. & Eisenman, R.N. Proteins encoded by the human c-myc oncogene: differential expression in neoplastic cells. Mol. Cell Biol. 4, 2486–2497 (1984).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Hann, S.R., Abrams, H.D., Rohrschneider, L.R. & Eisenman, R.N. Proteins encoded by v-myc and c-myc oncogenes: identification and localization in acute leukemia virus transformants and bursal lymphoma cell lines. Cell 34, 789–798 (1983).

    Article  CAS  PubMed  Google Scholar 

  33. Delgoffe, G.M. et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30, 832–844 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bar-Peled, L., Schweitzer, L.D., Zoncu, R. & Sabatini, D.M. Ragulator is a GEF for the rag GTPases that signal amino acid levels to mTORC1. Cell 150, 1196–1208 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Han, J.M. et al. Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149, 410–424 (2012).

    CAS  PubMed  Google Scholar 

  36. Bonfils, G. et al. Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol. Cell 46, 105–110 (2012).

    Article  CAS  PubMed  Google Scholar 

  37. Smith, K.A. & Cantrell, D.A. Interleukin 2 regulates its own receptors. Proc. Natl. Acad. Sci. USA 82, 864–868 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kurts, C. et al. Constitutive class I-restricted exogenous presentation of self antigens in vivo. J. Exp. Med. 184, 923–930 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Pircher, H., Bürki, K., Lang, R., Hengartner, H. & Zinkernagel, R.M. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature 342, 559–561 (1989).

    Article  CAS  PubMed  Google Scholar 

  40. Holman, G.D. et al. Cell surface labeling of glucose transporter isoform GLUT4 by bis-mannose photolabel. Correlation with stimulation of glucose transport in rat adipose cells by insulin and phorbol ester. J. Biol. Chem. 265, 18172–18179 (1990).

    CAS  PubMed  Google Scholar 

  41. Pearce, E.L. & Shen, H. Generation of CD8 T cell memory is regulated by IL-12. J. Immunol. 179, 2074–2081 (2007).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank G. Holman (University of Bath) for anti-Glut1; H. Shen (University of Pennsylvania) for L. monocytogenes; L. Chen for help in the initial characterization of amino-acid transporters expressed by CTLs; members of the Biological Services Unit; R. Clarke of the Flow Cytometry Facility; and members of the D.A.C. laboratory and S. Arthur for critical reading of the manuscript. Supported by the Wellcome Trust (065975/Z/01/A and 097418/Z/11Z to D.A.C., and WT094226 to P.M.T.) and the Intramural Research Program of the National Institute Child Health and Human Development of the US National Institutes of Health.

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L.V.S., all in vitro and most in vivo experiments; J.R., in vivo immunization with NP-OVA and infection with L. monocytogenes; E.E., genomic PCR analysis of Slc7a5fl/flCD4-Cre mice; Y.-B.S., generation of Slc7a5fl/fl mice; P.M.T., conceptual design; and D.A.C., conceptual design and manuscript authorship.

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Correspondence to Doreen A Cantrell.

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Sinclair, L., Rolf, J., Emslie, E. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14, 500–508 (2013). https://doi.org/10.1038/ni.2556

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